A cyclin-dependent kinase (CDK) is a serine/threonine kinase and binds to a cyclin to form a complex which has kinase activity and substrate specificity. A CDK is known as a kinase regulating the cell cycle through an interaction with various cyclins. Further, a CDK is also involved in transcription regulation, epigenetic regulation, metabolism regulation, stem cell self-renewal, neuronal function, etc. (Lim S, et al., Development, 2013, 140(15): 3079-93).
There are 16 CDK isotypes and they play an important role in the cell cycle regulation or transcription regulation depending on the isotype. In particular, CDK1 and CDK2 among CDKs regulating the cell cycle play an important role in a mitosis. CDK2 induces DNA synthesis in S phase and the progression through the cell cycle. CDK1 is involved in the formation of many factors to drive M phase. Accordingly, abnormality of a CDK may cause various cancers. An anticancer agent targeted to CDK abnormality will be effective in treating blood cancers including acute lymphoblastic leukemia (ALL), chronic lymphoblastic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), multiple myeloma (MM), Hodgkin's lymphoma, and non-Hodgkin's lymphoma, and solid cancers including non-small cell lung cancer, small cell lung cancer, gastric cancer, pancreas cancer, glioma, colon cancer, breast cancer, head and neck squamous cell cancer, liver cancer, melanoma, uterine cancer, prostate cancer, ovarian cancer, thyroid cancer, biliary tract cancer, gallbladder cancer, bladder cancer, kidney cancer, esophageal cancer, etc. (Pitts T M, et al., Pharmacol Ther., 2014, 142(2): 58-69).
CDK5, which is not involved in the regulation of the cell cycle or a transcription, is mostly distributed in a brain, and is activated by binding to p25 which is stable in a cell, resulting in continuous activity and thus various degenerative brain diseases. A substance inhibiting CDK5 activity will be useful for treating Alzheimer's disease, Parkinson's disease, and Huntington's chorea. In particular, Alzheimer's disease is caused by the neurodegeneration which is the result of the formation of neurofibrillary tangles (NFT) and amyloid plaques, and CDK5 is important for their formation. CDK5 phosphorylates the serin or threonine residues at Thr181, Ser199, Ser202, Thr212, Ser214, Thr231, Ser235, Ser396, and Ser404 of tau protein and tau protein hyperphosphorylated by CDK5 forms a neurofibrillary tangle (NFT). Amyloid plaque is formed by accumulation of Aβ (amyloid beta protein) which is produced by degradation of Amyloid precursor protein (APP) by the aspartic proteases, β-secretase and γ-secretase, in a brain. In this regard, CDK5 phosphorylates Thr668 residue of APP so that APP can be degraded by β-secretase. Therefore, it is necessary to develop a compound which can inhibit CDK5 activity and thus prevent and treat degenerative brain diseases such as Alzheimer's disease caused by excessive action of CDK5 (Cruz J C, et al., Trends Mol Med., 2004, 10(9): 452-8).